rs144426436

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_012156.2(EPB41L1):c.1643A>G(p.Lys548Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00375 in 1,613,530 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 24 hom. )

Consequence

EPB41L1
NM_012156.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.65

Publications

8 publications found

Variant links:

Genes affected

EPB41L1 (HGNC:3378): (erythrocyte membrane protein band 4.1 like 1) Erythrocyte membrane protein band 4.1 (EPB41) is a multifunctional protein that mediates interactions between the erythrocyte cytoskeleton and the overlying plasma membrane. The encoded protein binds and stabilizes D2 and D3 dopamine receptors at the neuronal plasma membrane. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]

EPB41L1 Gene-Disease associations (from GenCC):

autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
intellectual disability, autosomal dominant 11
Inheritance: AD Classification: LIMITED Submitted by: G2P

EPB41L1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010875225).

BP6

Variant 20-36198016-A-G is Benign according to our data. Variant chr20-36198016-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 414 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012156.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EPB41L1	NM_012156.2	MANE Select	c.1643A>G	p.Lys548Arg	missense	Exon 14 of 22	NP_036288.2
EPB41L1	NM_001433605.1		c.1643A>G	p.Lys548Arg	missense	Exon 14 of 23	NP_001420534.1
EPB41L1	NM_001258329.1		c.1643A>G	p.Lys548Arg	missense	Exon 15 of 23	NP_001245258.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EPB41L1	ENST00000338074.7	TSL:1 MANE Select	c.1643A>G	p.Lys548Arg	missense	Exon 14 of 22	ENSP00000337168.2
EPB41L1	ENST00000373946.7	TSL:1	c.1643A>G	p.Lys548Arg	missense	Exon 15 of 23	ENSP00000363057.4
EPB41L1	ENST00000202028.9	TSL:1	c.1421A>G	p.Lys474Arg	missense	Exon 13 of 20	ENSP00000202028.5

Frequencies

GnomAD3 genomes

AF:

0.00272

AC:

413

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00707

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00425

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00284

AC:

707

AN:

248540

AF XY:

0.00280

show subpopulations

Gnomad AFR exome

AF:

0.000633

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.000898

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00921

Gnomad NFE exome

AF:

0.00382

Gnomad OTH exome

AF:

0.00280

GnomAD4 exome

AF:

0.00386

AC:

5643

AN:

1461356

Hom.:

Cov.:

AF XY:

0.00375

AC XY:

2724

AN XY:

726986

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33472

American (AMR)

AF:

0.00134

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.000765

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0105

AC:

556

AN:

53064

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00435

AC:

4839

AN:

1111892

Other (OTH)

AF:

0.00238

AC:

144

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

336

672

1007

1343

1679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

360

540

720

900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00272

AC:

414

AN:

152174

Hom.:

Cov.:

AF XY:

0.00276

AC XY:

205

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

41528

American (AMR)

AF:

0.000916

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00707

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00426

AC:

290

AN:

67996

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00324

Hom.:

Bravo

AF:

0.00226

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00263

AC:

319

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00376

EpiControl

AF:

0.00326

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EPB41L1: BS2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Oct 20, 2015

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EPB41L1-related disorder

Benign:1

Feb 27, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.031

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

2.7

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.58

REVEL

Benign

0.25

Sift

Benign

0.43

Sift4G

Benign

0.49

Polyphen

0.57

Vest4

0.27

MVP

0.83

MPC

0.31

ClinPred

0.015

GERP RS

4.0

PromoterAI

-0.049

Neutral

(source)

Varity_R

0.056

gMVP

0.21

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over